Optimized induction of mitochondrial apoptosis for chemotherapy-free treatment of BCR-ABL+acute lymphoblastic leukemia

Michaela Scherr, Hanna Kirchhoff, Karin Battmer, Katharina Wohlan, Chun-Wei Lee, Melanie Ricke-Hoch, Sergej Erschow, Edward Law, Arnold Kloos, Michael Heuser, Arnold Ganser, Denise Hilfiker-Kleiner, Olaf Heidenreich, Matthias Eder

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

BCR-ABL+acute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. We here characterize the curative potential of BH3-mimetics differentially targeting mitochondrial BCL2-family members using a combination therapy approach with dexamethasone and tyrosine kinase inhibitors targeting BCR-ABL. In BCR-ABL + ALL BH3-mimetics act by redistribution of mitochondrial activator BIM, which is strongly required for cytotoxicity of the BCL2-specific BH3-mimetic ABT-199, tyrosine kinase inhibitors (TKIs) and dexamethasone. BIM expression is enhanced by dexamethasone and TKIs and both synergize with ABT-199 in BCR-ABL + ALL. Triple combinations with ABT-199, dexamethasone and TKIs efficiently attenuate leukemia progression both in tissue culture and in primary cell xenotransplantation models. Notably, the dasatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL + mouse model. Finally, response to BH3-mimetics can be predicted for individual patients in a clinically relevant setting. These data demonstrate curative targeted and chemotherapy-free pharmacotherapy for BCR-ABL + ALL in a preclinical model. Clinical evaluation, in particular for patients not suitable for allogeneic SCT, is warranted.

Originele taal-2Engels
Pagina's (van-tot)1313-1323
Aantal pagina's11
TijdschriftLeukemia
Volume33
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - jun. 2019
Extern gepubliceerdJa

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